Is MSH6 p.Val80= (c.240A>G) pathogenic?

MSH6 p.Val80= (c.240A>G) is classified Conflicting classifications of pathogenicity in MSH6 (ClinVar, Conflicting submitters, 12 submitters; last evaluated 2025-12-22). Very rare (popmax 0.00866%, amr); Associated with Hereditary nonpolyposis colorectal neoplasms.

How common is MSH6 p.Val80= (c.240A>G) in the general population?

MSH6 p.Val80= (c.240A>G) is very rare (popmax 0.00866%, amr) (gnomAD).

MSH6 p.Val80=

Q: What condition is associated with MSH6 p.Val80= (c.240A>G)?

MSH6 p.Val80= (c.240A>G) is associated with Hereditary nonpolyposis colorectal neoplasms, Lynch syndrome, Lynch syndrome 5 (ClinVar).

c.240A>G · rs864622281 · VCV219856

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 12 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00866%, amr)

Conditions

Hereditary nonpolyposis colorectal neoplasms

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -1.9	GERP -3
Overall
CADD	6.521	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00866% Admixed American · 3/34,662 alleles

Filtering AF 0.00229% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00168%

Overall 0.00277% 40/1,443,500 alleles · very rare exomes 35/1,291,758 · genomes 5/151,742 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00866%	11,554
African / African-American	0.00599%	16,698
Remaining individualsnot grpmax-eligible	0.00361%	27,677
European (non-Finnish)	0.00273%	36,612
South Asian	0.00146%	68,358

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: MSH6
Protein: p.Val80=
Coding: c.240A>G
MANE Select: NM_000179
dbSNP: rs864622281
Type: single nucleotide variant
Location: chr2:47783473 (GRCh38)
Gene constraint: LOEUF 0.841 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.93 · 8 PDB
Residue 80: the 'disordered' region

Full MSH6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Hereditary nonpolyposis colorectal neoplasms — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Lynch syndrome Lynch syndrome 5 hereditary neoplastic syndrome

Similar variants

MSH6 p.Val80Ile Pathogenic ⚠ same residue
MSH6 c.3172+1G>T Likely pathogenic ★★★ same condition
MSH6 c.3438+1G>A Likely pathogenic ★★★ same condition
MSH6 c.3439-1G>T Likely pathogenic ★★★ same condition
MSH6 c.3439-2A>G Likely pathogenic ★★★ same condition
MSH6 c.3647-1G>A Pathogenic ★★★ same condition
MSH6 c.3647-2A>C Pathogenic ★★★ same condition
MSH6 c.4001+2T>C Pathogenic ★★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/msh6-p-val80 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown